The significance of cocaine abuse in society continues to grow as time continues to pass without a valid treatment that will decrease the likelihood of relapse. It is not necessarily the immediate effects of cocaine administration that cause such a long-lasting change. More likely, changes accumulate that increase relapse vulnerability during a significant period of abstinence from cocaine. Using a rat model of cocaine self-administration that closely resembles the patterns of human use, behavioral sensitization can be observed after long periods of abstinence following ten days of cocaine self-administration. Following abstinence, animals will work significantly harder to receive an injection of cocaine. The behavioral sensitization that occurs because of enforced abstinence can be observed after ten days, but is not seen after one day, and remains for at least ten days. It is therefore hypothesized, in this application, that behavioral sensitization, resulting from enforced abstinence, is accompanied by changes in protein expression in the mesolimbic areas of the brain that contribute to cocaine's reinforcing efficacy. The proteomic profiles of mesolimbic structures will be characterized across a time-course, including animals after 1, 10, and 100 days of abstinence following ten days of self-administration and controls responding for food. The protein alterations observed, especially those observed to persist through, or emerge during, abstinence may be the molecular manifestation of the observed behavioral phenomena. After describing protein changes, the mechanism by which these levels can be persistently altered will be examined. Histone modification, a long-term method of expression regulation within the cell, will be examined at the site of abstinence-responsive genes, as changes in histone acetylation levels are frequently associated with altered levels of expression. The identification of both functional protein changes and the mechanisms responsible for these changes has the potential to classify targets for development of new treatments for cocaine abuse and relapse. Cocaine use and abuse is a major societal problem that continues to grow as abuse and relapse rates remain high, and the public sector is forced to pay for a majority of cocaine's heath-related effects. By elucidating the specific mechanisms by which cocaine can exert effects long after the drug has left the body, potential therapies targeting these mechanisms may result.